Project 1 focuses on the ability of the transcription factor CREB in the nucleus accumbens (NAc) to regulate mood and motivational state. We have considerable evidence that increased CREB function in this brain region, which occurs under several conditions of stress, causes a decrease in an animal's sensitivity to emotional stimuli, regardless of whether the stimuli are aversive or rewarding. Reduced CREB function has the opposite effect. These findings suggest that CREB in the NAc may function as a key molecular gate between emotional stimuli and their behavioral responses. A possible relationship between this phenotype and symptoms of anhedonia and reduced motivation in depressed humans will be explored in further studies of animal models, including analysis of various stress models, sexual behavior, intra-cranial self-stimulation, and social interactions. Viral-mediated gene transfer and inducible, cell-targeted mutations in mice will be used in these experiments. Another goal of the proposed studies is to investigate the cellular specificity of stress regulation of CREB in the NAc, and its possible modification by antidepressant treatments. Related studies will explore the molecular mechanisms by which stress and antidepressants regulate CREB in this brain region. A third goal of the proposed studies is to identify target genes through which CREB produces these effects on mood and motivation. The genes encoding the opioid peptide dynorphin and the AMPA glutamate receptor subunit GluR1 are two such targets of CREB that will be examined in this Project. Additional targets will be identified with DNA microarrays. Among the targets identified in initial array experiments are BDNF and NPAS2, the major gene products of interest in Projects 2 and 4, respectively. As stated earlier, CREB function is a major theme in this Center. All of the subsequent Projects of this Grant represent extensions of our central hypothesis that CREB in the NAc is a key regulator of hedonic or affective state. Subsequent Projects extend this theme by examining other molecular constituents of NAc neurons, which are regulated by CREB and help control CREB activity, for their role in this complex behavioral, phenotype. In addition, the other Projects explore a related role for CREB in certain hypothalamic (Project 3) and VTA(ventral tegmental area) (Project 2) neurons, which, along with the NAc, form a neural circuit controlling appetitive behavior.